HIV-1 enters the Central Nervous System (CNS) after the primary infection and contributes to the neurological deficits observed in patients. Moderate to high viral titers are found in the CNS due to the fact that the majority of anti-retroviral agents are unable to achieve sufficient levels in the brain. The Blood Brain Barrier (BBB) possesses tight junctions and various Multi-Drug Resistance (MDR) transporters such as P-glycoprotein (Pgp) and Multi-drug Resistance Associated Protein (MRP-2), which serve to significantly minimize brain anti-retroviral drug delivery to the brain. Thus, the hypothesis of this therapeutic intervention proposal is that anti-retroviral drug delivery to the brain can be enhanced in order to manageHIV-1 related neuroinvasion by reversibly opening tight junctions and by modulation of MDR (P-glycoprotein,MRP) mediated efflux at the BBB. In order to test this hypothesis, the following three specific aims (SA) will be pursued SA1 To examine the ability of Zonula Occludens Toxin (Zot) to enhance the BBB transport, brain uptake and activity of two "model" antiretroviral agents (AZT, zidovudine) using cell culture techniques and the SCID mice. Preliminary studies have shown that Zot is capable of reversibly opening tight junctions in the BBB, as well as significantly (p < 0 05) increasing brain levels of hydrophilic and hydrophobic agents (e g, paclitaxel, doxorubicin).Uninfected SCID mice and SCID mice inoculated with HIV-1 infected monocytes in the brain caudate and putamen will be used. Antiretroviral brain levels and viral titers will be determined. SA 2 To examine the effect of MDR modulation on the BBB transport, brain uptake and activity of AZT and saquinavir (substrates of MRP-1 and Pgp) two "model" anti-retroviral agents using cell culture techniques and the SCID mouse model. To examine the effect of MDR modulation on the in vitro BBB transport and brain distribution of on AZT and saquinavir (substrates of MRp-2 and Pgp)using cell culture techniques and the SCID mice SA3.To examine the concomitant effect of Zot and the MDR inhibitors on the BBB transport, brain uptake and activity of AZT and saquinavir using SCID mice. Obtaining therapeutic CNS levels of anti-retroviral agents is essential to minimizing HIV-1 in the CNS. As such, this proposal offers a viable approach to address this complication of HIV/AIDS.